INSIGHTS | P E R S P E C T I V E S
“…approaches to target … oxytocin… will hopefully lead to improving social function in ASD…” social cognition but not with ASD diagnosis, which suggests that circulating oxytocin and oxytocin receptor sequence may be useful biomarkers to identify individuals most responsive to oxytocin therapies (12). The heterogeneity of ASD makes identification of therapies based on diagnoses difficult. That oxytocin was effective in Cntnap2 mutant mice with compromised oxytocin signaling does not imply that oxytocin will be effective for all ASD populations. The U.S. National Institute of Mental Health (NIMH) is encouraging a classification system based on Research Domain Criteria, which stratifies clinical populations based on behavioral dimensions and biological mechanisms. NIMH is also requiring evidence of target engagement for clinical trial funding involving oxytocin. As an example, oxytocin improved social emotion detection in ASD males and modulated activity in the brain’s insular cortex, thus demonstrating a functional impact on an impaired neural system (13). Incorporating these suggestions will likely lead to improved oxytocin-based therapies in ASD.
Silvio O. Conte Center for Oxytocin and Social Cognition, Department of Psychiatry, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA. E-mail: [email protected]
826
Efficient brain penetration and activation of oxytocin receptors throughout the social neural network, as occurs after endogenous oxytocin release, is potentially an important limitation to the current oxytocin therapies. The next generation of therapeutics may bypass this obstacle (14). Pharmacologically enhancing endogenous oxytocin release, or developing small-molecule agonists and positive allosteric modulators, may be most effective for engaging the brain’s natural oxytocin system to improve social cognition. For example, acute melanocortin-4 receptor (MC4R) agonist treatment potentiates oxytocin release in brain reward centers (including the ventral striatum) and facilitates oxytocinmediated social attachment in voles (14). Activating MC4Rs during the first postnatal week enhances later social relationships in these animals as well (15). Acute stimulation of MC4R also rescues social deficits in the Cntnap2 mutant mouse (2). Further, social impairment in this mouse model was rescued by a gene therapy strategy involving the expression of designer receptors exclusively activated by designer drugs (DREADDs) in oxytocin neurons, an approach that may one day be feasible in humans. Oxytocin remains an exciting target for improving social function. However, investigations into its potential therapeutic application are still in the early stages. Some would argue that the therapeutic value of intranasal oxytocin remains tenuous. Indeed, there are insufficient data for physicians to prescribe oxytocin to patients or for parents to seek oxytocin for their autistic child. Nonetheless, increasing information on mechanisms from animal studies, optimizing current therapeutic paradigms, and developing next-generation approaches to target the oxytocin system will hopefully lead to improving social function in ASD and other psychiatric disorders. ■ REFERENCES
1. E. Anagnostou et al., Brain Res. 1580, 188 (2014). 2. O. Peñagarikano et al., Sci. Transl. Med. 7, 271ra8 (2015). 3. A. J. Guastella et al., J. Child Psychol. Psychiatry 10.1111/ jcpp.12305 (2014). 4. S. M. Freeman, K. Inoue, A. L. Smith, M. M. Goodman, L. J. Young, Psychoneuroendocrinology 45, 128 (2014). 5. S. F. Owen et al., Nature 500, 458 (2013). 6. I. Gordon et al., Proc. Natl. Acad. Sci. U.S.A. 110, 20953 (2013). 7. R. Tyzio et al., Science 343, 675 (2014). 8. H. Huang et al., Neuropsychopharmacology 39, 1102 (2014). 9. B. L. Teng et al., Neuropharmacology 72, 187 (2013). 10. D. LoParo, I. D. Waldman, Mol. Psychiatry 10.1038/ mp.2014.77 (2014). 11. D. H. Skuse et al., Proc. Natl. Acad. Sci. U.S.A. 111, 1987 (2014). 12. K. J. Parker et al., Proc. Natl. Acad. Sci. U.S.A. 111, 12258 (2014). 13. Y. Aoki et al., Brain 137, 3073 (2014). 14. M. E. Modi et al., Neuropsychopharmacology 10.1038/ npp.2015.35 (2015). 15. C. E. Barrett et al., Neuropharmacology 85, 357 (2014). 10.1126/science.aaa8120
CELL BIOLOGY
Pancreas micromanages autophagy Nutrient-sensing β cells degrade insulin when blood glucose is low By Guy A. Rutter
C
ells need to find ways of surviving when times are hard. One way of dealing with nutrient scarcity is to digest intracellular constituents, providing a source of amino acids that can be used to synthesize proteins that are essential for survival (1). This process of autophagy (2), however, poses a problem for the body’s specialized fuel-sensing cells. β cells within the pancreatic islet respond to blood glucose concentration—when it rises after a meal, these cells release insulin; otherwise, under basal conditions (between meals), the cells are in a “starvation”-like state (3). So how do they maintain a normal turnover of intracellular components during this metabolic deprivation? Why don’t they eat themselves as other cells would? At the very least, autophagy under basal conditions could compromise the ability to respond optimally to fluctuations in blood glucose, posing a health risk. On page 878 of this issue, Goginashvili et al. (4) show how β cells avoid inappropriate autophagy, and describe a form of this process tailored to the needs of these cells. Classical autophagy is a complex process regulated by multiple mechanisms. In starvation, the ratio of adenosine triphosphate (ATP) to adenosine diphosphate (ADP) falls, as does the ratio of ATP to adenosine monophosphate (AMP). These changes stimulate AMP-activated protein kinase (AMPK) (5) and a downstream signaling pathway that eventually inhibits mechanistic target of rapamycin complex 1 (mTORC1) (6). The outcome is the activation of autophagy. Most cells, however, usually maintain a high ATP/ADP ratio such that autophagy is suppressed most of the time. Autophagy has an important role to play in replacing exhausted cellular components, such as mitochondria and other membrane-bound organelles. Previous studies have shown that maintaining minimal levels of autophagy is important sciencemag.org SCIENCE
20 FEBRUARY 2015 • VOL 347 ISSUE 6224
Published by AAAS
Downloaded from www.sciencemag.org on February 19, 2015
mice. This switch is impaired in ASD-like mice, and oxytocin-mediated restoration of this process alleviates social deficits (7). Parallel animal and human studies are also needed to determine the developmental consequences of chronic oxytocin exposure. For these investigations, care must be taken to avoid detrimentally affecting brain maturation, as early chronic intranasal administration apparently reduces oxytocin receptor expression and social behavior in normal mice (8). An intermittent oxytocin treatment regimen may be preferable over chronic exposure (9). Whether a compromised oxytocin system contributes to ASDs is unclear. A metaanalysis found that variation in the oxytocin receptor gene associates with ASD (10), although individual studies fail to report associations (11, 12). Rather, it appears that variation in the oxytocin system contributes to social phenotypes, regardless of diagnosis. Blood oxytocin concentration and oxytocin receptor genotype strongly associate with
ILLUSTRATION: V. ALTOUNIAN/SCIENCE
Pancreatic β cell Other cell type in β cells because deletion of the wise, this suggests that insulin is not gene encoding autophagy-related 7 mistargeted toward the constitutive Low glucose (Atg7), required for autophagy, in secretory pathway under these con(starvation) these cells leads to diabetes in the ditions, instead of being packaged mouse (7, 8). Thus, it has been asinto mature secretory granules. sumed that β cells, like other cell The findings of Goginashvili et types, use “classical” autophagy (or al. provide an answer to interesting “crinophagy”) to degrade aging inconundrums, including the observap38δ/PKD1 AMPK sulin-containing secretory granules, tion that genetic deletion of AMPK and that this process maintains (or the upstream kinase liver kinase stable insulin levels (9). GoginashB1) has relatively minor effects on Insulin granule vili et al. suggest that a separate autophagy in β cells (12). However, destruction process—or at least a process that is that the stimulation of autophagy controlled separately from classical activates insulin release still leaves Release autophagy—plays a dominant role many questions to be answered. Is nutrients in β cells (see the figure). this simply a result of increasing the Remarkably, and in contrast to number of secretory granules, or is mTORC1 mTORC1 non–nutrient-sensing cells (including their localization with respect to the activation inactivation human embryonic kidney cells and plasma membrane (where they fuse plasma cells), for β cells, starvation to release insulin) also changed? Are produces a decrease in the usual inother “triggering” signals for secreBlocks Stimulates dices of autophagy, notably the incortion (e.g., ATP/ADP, intracellular autophagy autophagy poration of microtubule-associated calcium concentration, etc.) also elprotein 1 light chain 3B into memevated? It is also not clear how p38δ, branes. Instead, Goginashvili et al. oband therefore PKD1, are regulated Destruction of No destruction of cell constituents cell constituents served a different form of autophagy by nutrients. by which insulin-containing granules The global health care burden (and not other organelles) are prefof diabetes is hard to overestimate, Release erentially degraded by lysosomes at with >380 million individuals curnutrients low extracellular glucose concentrarently affected worldwide (13) and tions. The authors call this process a cost to the taxpayer in the United Cell survival starvation-induced nascent granule States alone of ~$250 billion per degradation (SINGD). Here, the reAutophagy or not? Under low glucose conditions (starvation), the degradayear (14). The incidence of the disleased amino acids resulting from tion of insulin granules in β cells leads to the production of amino acids, the ease is predicted to rise to >500 milthe destruction of insulin granules in local activation of mTORC1, and suppression of autophagy, which removes a lion by 2035, with most new cases the cell’s lysosomes activate mTORC1, signal for insulin release and ensures cell survival. In non–nutrient-sensing due to type 2 diabetes. The study which translocates to lysosomal memcells, the same condition activates autophagy to ensure survival. of Goginashvili et al. suggests that branes and suppresses wmore general pharmacological activation of classicellular autophagy. Thus, a highly localized or SINGD has deleterious consequences for cal autophagy in β cells is likely to be probchange in an intracellular metabolic signal, regulated insulin secretion. Indeed, insulin lematic or even dangerous, as it is likely as previously seen in β cells (10), controls the release increased at low glucose concentrato enhance secretion when blood glucose ultimate fate of both newly synthesized insution in the presence of the mTORC1 inhibiconcentration is low and thus run the risk lin and other cellular constituents to ensure tor rapamycin, or an artificial autophagy of hypoglycemia. On the other hand, the that insulin granule turnover occurs without activator, tat-beclin1. These findings show identification of SINGD and its regulation jeopardizing other organelles. the importance of suppressing autophagy by PKD1 may provide a useful therapeutic This mechanism may also provide a under starvation conditions. target to improve insulin release in some means of ensuring that when blood glucose How is the balance of SINGD and ausettings. ■ concentration is low, key fuel sensing systophagy controlled at the molecular level? REFERENCES tems in the β cell—notably mitochondrial Goginashvili et al. implicate protein kinase 1. D. G. Hardie, Science 331, 410 (2011). metabolism—are not activated (to syntheD1 (PKD1) in the control of SINGD. PKD1 2. S. L. Clark Jr., J. Biophys. Biochem. Cytol. 3, 349 (1957). size ATP) by the released amino acids. In is thought to regulate insulin release (11). 3. G. A. Rutter, T. J. Pullen, D. J. Hodson, A. Martinez-Sanchez, Biochem. J. 66, 202 (2015). this way, the closure of ATP-sensitive K+ Thus, inactivation of the enzyme p38δ, 4. A. Goginashvili et al., Science 347, 878 (2015). channels at the cell surface, membrane dewhich phosphorylates and inactivates 5. G. A. Rutter, G. da Silva Xavier, I. Leclerc, Biochem. J. 375, 1 polarization, and the activation of calcium PKD1, decreased SINGD, but increased clas(2003). influx into the cell (3)—a cascade that trigsical autophagy in mouse β cells. 6. K. Inoki, T. Zhu, K. L. Guan, Cell 115, 577 (2003). 7. C. Ebato et al., Cell Metab. 8, 325 (2008). gers insulin release—is avoided. How exactly are autophagy and enhanced 8. H. S. Jung et al., Cell Metab. 8, 318 (2008). Given the existence of such a complex insulin release related? Using diazoxide, a 9. B. J. Marsh et al., Mol. Endocrinol. 21, 2255 (2007). and finely balanced system, it should be no compound that prevents cell depolariza10. H. J. Kennedy et al., J. Biol. Chem. 274, 13281 (1999). 11. G. Sumara et al., Cell 136, 235 (2009). surprise that interference with autophagy tion and calcium influx, Goginashvili et 12. M. Kone et al., FASEB J. 28, 4972 (2014). al. show that a catastrophic event such as 13. L. Guariguata et al., Diabetes Res. Clin. Pract. 103, 137 cell death and lysis (which would allow in(2014). Section of Cell Biology and Functional Genomics, Division of sulin to leach out of the cell) is unlikely to 14. American Diabetes Association, Diabetes Care 36, 1033 Diabetes, Endocrinology and Metabolism, Imperial College (2013). be the explanation for enhanced insulin seLondon, Hammersmith Hospital, London W12 0NN, UK. cretion when autophagy is activated. Like10.1126/science.aaa6810 E-mail: [email protected] SCIENCE sciencemag.org
20 FEBRUARY 2015 • VOL 347 ISSUE 6224
Published by AAAS
827
Pancreas micromanages autophagy Guy A. Rutter Science 347, 826 (2015); DOI: 10.1126/science.aaa6810
This copy is for your personal, non-commercial use only.
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The following resources related to this article are available online at www.sciencemag.org (this information is current as of February 19, 2015 ): Updated information and services, including high-resolution figures, can be found in the online version of this article at: http://www.sciencemag.org/content/347/6224/826.full.html A list of selected additional articles on the Science Web sites related to this article can be found at: http://www.sciencemag.org/content/347/6224/826.full.html#related This article cites 14 articles, 6 of which can be accessed free: http://www.sciencemag.org/content/347/6224/826.full.html#ref-list-1 This article appears in the following subject collections: Cell Biology http://www.sciencemag.org/cgi/collection/cell_biol
Science (print ISSN 0036-8075; online ISSN 1095-9203) is published weekly, except the last week in December, by the American Association for the Advancement of Science, 1200 New York Avenue NW, Washington, DC 20005. Copyright 2015 by the American Association for the Advancement of Science; all rights reserved. The title Science is a registered trademark of AAAS.
Downloaded from www.sciencemag.org on February 19, 2015
Permission to republish or repurpose articles or portions of articles can be obtained by following the guidelines here.
“…approaches to target … oxytocin… will hopefully lead to improving social function in ASD…” social cognition but not with ASD diagnosis, which suggests that circulating oxytocin and oxytocin receptor sequence may be useful biomarkers to identify individuals most responsive to oxytocin therapies (12). The heterogeneity of ASD makes identification of therapies based on diagnoses difficult. That oxytocin was effective in Cntnap2 mutant mice with compromised oxytocin signaling does not imply that oxytocin will be effective for all ASD populations. The U.S. National Institute of Mental Health (NIMH) is encouraging a classification system based on Research Domain Criteria, which stratifies clinical populations based on behavioral dimensions and biological mechanisms. NIMH is also requiring evidence of target engagement for clinical trial funding involving oxytocin. As an example, oxytocin improved social emotion detection in ASD males and modulated activity in the brain’s insular cortex, thus demonstrating a functional impact on an impaired neural system (13). Incorporating these suggestions will likely lead to improved oxytocin-based therapies in ASD.
Silvio O. Conte Center for Oxytocin and Social Cognition, Department of Psychiatry, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA. E-mail: [email protected]
826
Efficient brain penetration and activation of oxytocin receptors throughout the social neural network, as occurs after endogenous oxytocin release, is potentially an important limitation to the current oxytocin therapies. The next generation of therapeutics may bypass this obstacle (14). Pharmacologically enhancing endogenous oxytocin release, or developing small-molecule agonists and positive allosteric modulators, may be most effective for engaging the brain’s natural oxytocin system to improve social cognition. For example, acute melanocortin-4 receptor (MC4R) agonist treatment potentiates oxytocin release in brain reward centers (including the ventral striatum) and facilitates oxytocinmediated social attachment in voles (14). Activating MC4Rs during the first postnatal week enhances later social relationships in these animals as well (15). Acute stimulation of MC4R also rescues social deficits in the Cntnap2 mutant mouse (2). Further, social impairment in this mouse model was rescued by a gene therapy strategy involving the expression of designer receptors exclusively activated by designer drugs (DREADDs) in oxytocin neurons, an approach that may one day be feasible in humans. Oxytocin remains an exciting target for improving social function. However, investigations into its potential therapeutic application are still in the early stages. Some would argue that the therapeutic value of intranasal oxytocin remains tenuous. Indeed, there are insufficient data for physicians to prescribe oxytocin to patients or for parents to seek oxytocin for their autistic child. Nonetheless, increasing information on mechanisms from animal studies, optimizing current therapeutic paradigms, and developing next-generation approaches to target the oxytocin system will hopefully lead to improving social function in ASD and other psychiatric disorders. ■ REFERENCES
1. E. Anagnostou et al., Brain Res. 1580, 188 (2014). 2. O. Peñagarikano et al., Sci. Transl. Med. 7, 271ra8 (2015). 3. A. J. Guastella et al., J. Child Psychol. Psychiatry 10.1111/ jcpp.12305 (2014). 4. S. M. Freeman, K. Inoue, A. L. Smith, M. M. Goodman, L. J. Young, Psychoneuroendocrinology 45, 128 (2014). 5. S. F. Owen et al., Nature 500, 458 (2013). 6. I. Gordon et al., Proc. Natl. Acad. Sci. U.S.A. 110, 20953 (2013). 7. R. Tyzio et al., Science 343, 675 (2014). 8. H. Huang et al., Neuropsychopharmacology 39, 1102 (2014). 9. B. L. Teng et al., Neuropharmacology 72, 187 (2013). 10. D. LoParo, I. D. Waldman, Mol. Psychiatry 10.1038/ mp.2014.77 (2014). 11. D. H. Skuse et al., Proc. Natl. Acad. Sci. U.S.A. 111, 1987 (2014). 12. K. J. Parker et al., Proc. Natl. Acad. Sci. U.S.A. 111, 12258 (2014). 13. Y. Aoki et al., Brain 137, 3073 (2014). 14. M. E. Modi et al., Neuropsychopharmacology 10.1038/ npp.2015.35 (2015). 15. C. E. Barrett et al., Neuropharmacology 85, 357 (2014). 10.1126/science.aaa8120
CELL BIOLOGY
Pancreas micromanages autophagy Nutrient-sensing β cells degrade insulin when blood glucose is low By Guy A. Rutter
C
ells need to find ways of surviving when times are hard. One way of dealing with nutrient scarcity is to digest intracellular constituents, providing a source of amino acids that can be used to synthesize proteins that are essential for survival (1). This process of autophagy (2), however, poses a problem for the body’s specialized fuel-sensing cells. β cells within the pancreatic islet respond to blood glucose concentration—when it rises after a meal, these cells release insulin; otherwise, under basal conditions (between meals), the cells are in a “starvation”-like state (3). So how do they maintain a normal turnover of intracellular components during this metabolic deprivation? Why don’t they eat themselves as other cells would? At the very least, autophagy under basal conditions could compromise the ability to respond optimally to fluctuations in blood glucose, posing a health risk. On page 878 of this issue, Goginashvili et al. (4) show how β cells avoid inappropriate autophagy, and describe a form of this process tailored to the needs of these cells. Classical autophagy is a complex process regulated by multiple mechanisms. In starvation, the ratio of adenosine triphosphate (ATP) to adenosine diphosphate (ADP) falls, as does the ratio of ATP to adenosine monophosphate (AMP). These changes stimulate AMP-activated protein kinase (AMPK) (5) and a downstream signaling pathway that eventually inhibits mechanistic target of rapamycin complex 1 (mTORC1) (6). The outcome is the activation of autophagy. Most cells, however, usually maintain a high ATP/ADP ratio such that autophagy is suppressed most of the time. Autophagy has an important role to play in replacing exhausted cellular components, such as mitochondria and other membrane-bound organelles. Previous studies have shown that maintaining minimal levels of autophagy is important sciencemag.org SCIENCE
20 FEBRUARY 2015 • VOL 347 ISSUE 6224
Published by AAAS
Downloaded from www.sciencemag.org on February 19, 2015
mice. This switch is impaired in ASD-like mice, and oxytocin-mediated restoration of this process alleviates social deficits (7). Parallel animal and human studies are also needed to determine the developmental consequences of chronic oxytocin exposure. For these investigations, care must be taken to avoid detrimentally affecting brain maturation, as early chronic intranasal administration apparently reduces oxytocin receptor expression and social behavior in normal mice (8). An intermittent oxytocin treatment regimen may be preferable over chronic exposure (9). Whether a compromised oxytocin system contributes to ASDs is unclear. A metaanalysis found that variation in the oxytocin receptor gene associates with ASD (10), although individual studies fail to report associations (11, 12). Rather, it appears that variation in the oxytocin system contributes to social phenotypes, regardless of diagnosis. Blood oxytocin concentration and oxytocin receptor genotype strongly associate with
ILLUSTRATION: V. ALTOUNIAN/SCIENCE
Pancreatic β cell Other cell type in β cells because deletion of the wise, this suggests that insulin is not gene encoding autophagy-related 7 mistargeted toward the constitutive Low glucose (Atg7), required for autophagy, in secretory pathway under these con(starvation) these cells leads to diabetes in the ditions, instead of being packaged mouse (7, 8). Thus, it has been asinto mature secretory granules. sumed that β cells, like other cell The findings of Goginashvili et types, use “classical” autophagy (or al. provide an answer to interesting “crinophagy”) to degrade aging inconundrums, including the observap38δ/PKD1 AMPK sulin-containing secretory granules, tion that genetic deletion of AMPK and that this process maintains (or the upstream kinase liver kinase stable insulin levels (9). GoginashB1) has relatively minor effects on Insulin granule vili et al. suggest that a separate autophagy in β cells (12). However, destruction process—or at least a process that is that the stimulation of autophagy controlled separately from classical activates insulin release still leaves Release autophagy—plays a dominant role many questions to be answered. Is nutrients in β cells (see the figure). this simply a result of increasing the Remarkably, and in contrast to number of secretory granules, or is mTORC1 mTORC1 non–nutrient-sensing cells (including their localization with respect to the activation inactivation human embryonic kidney cells and plasma membrane (where they fuse plasma cells), for β cells, starvation to release insulin) also changed? Are produces a decrease in the usual inother “triggering” signals for secreBlocks Stimulates dices of autophagy, notably the incortion (e.g., ATP/ADP, intracellular autophagy autophagy poration of microtubule-associated calcium concentration, etc.) also elprotein 1 light chain 3B into memevated? It is also not clear how p38δ, branes. Instead, Goginashvili et al. oband therefore PKD1, are regulated Destruction of No destruction of cell constituents cell constituents served a different form of autophagy by nutrients. by which insulin-containing granules The global health care burden (and not other organelles) are prefof diabetes is hard to overestimate, Release erentially degraded by lysosomes at with >380 million individuals curnutrients low extracellular glucose concentrarently affected worldwide (13) and tions. The authors call this process a cost to the taxpayer in the United Cell survival starvation-induced nascent granule States alone of ~$250 billion per degradation (SINGD). Here, the reAutophagy or not? Under low glucose conditions (starvation), the degradayear (14). The incidence of the disleased amino acids resulting from tion of insulin granules in β cells leads to the production of amino acids, the ease is predicted to rise to >500 milthe destruction of insulin granules in local activation of mTORC1, and suppression of autophagy, which removes a lion by 2035, with most new cases the cell’s lysosomes activate mTORC1, signal for insulin release and ensures cell survival. In non–nutrient-sensing due to type 2 diabetes. The study which translocates to lysosomal memcells, the same condition activates autophagy to ensure survival. of Goginashvili et al. suggests that branes and suppresses wmore general pharmacological activation of classicellular autophagy. Thus, a highly localized or SINGD has deleterious consequences for cal autophagy in β cells is likely to be probchange in an intracellular metabolic signal, regulated insulin secretion. Indeed, insulin lematic or even dangerous, as it is likely as previously seen in β cells (10), controls the release increased at low glucose concentrato enhance secretion when blood glucose ultimate fate of both newly synthesized insution in the presence of the mTORC1 inhibiconcentration is low and thus run the risk lin and other cellular constituents to ensure tor rapamycin, or an artificial autophagy of hypoglycemia. On the other hand, the that insulin granule turnover occurs without activator, tat-beclin1. These findings show identification of SINGD and its regulation jeopardizing other organelles. the importance of suppressing autophagy by PKD1 may provide a useful therapeutic This mechanism may also provide a under starvation conditions. target to improve insulin release in some means of ensuring that when blood glucose How is the balance of SINGD and ausettings. ■ concentration is low, key fuel sensing systophagy controlled at the molecular level? REFERENCES tems in the β cell—notably mitochondrial Goginashvili et al. implicate protein kinase 1. D. G. Hardie, Science 331, 410 (2011). metabolism—are not activated (to syntheD1 (PKD1) in the control of SINGD. PKD1 2. S. L. Clark Jr., J. Biophys. Biochem. Cytol. 3, 349 (1957). size ATP) by the released amino acids. In is thought to regulate insulin release (11). 3. G. A. Rutter, T. J. Pullen, D. J. Hodson, A. Martinez-Sanchez, Biochem. J. 66, 202 (2015). this way, the closure of ATP-sensitive K+ Thus, inactivation of the enzyme p38δ, 4. A. Goginashvili et al., Science 347, 878 (2015). channels at the cell surface, membrane dewhich phosphorylates and inactivates 5. G. A. Rutter, G. da Silva Xavier, I. Leclerc, Biochem. J. 375, 1 polarization, and the activation of calcium PKD1, decreased SINGD, but increased clas(2003). influx into the cell (3)—a cascade that trigsical autophagy in mouse β cells. 6. K. Inoki, T. Zhu, K. L. Guan, Cell 115, 577 (2003). 7. C. Ebato et al., Cell Metab. 8, 325 (2008). gers insulin release—is avoided. How exactly are autophagy and enhanced 8. H. S. Jung et al., Cell Metab. 8, 318 (2008). Given the existence of such a complex insulin release related? Using diazoxide, a 9. B. J. Marsh et al., Mol. Endocrinol. 21, 2255 (2007). and finely balanced system, it should be no compound that prevents cell depolariza10. H. J. Kennedy et al., J. Biol. Chem. 274, 13281 (1999). 11. G. Sumara et al., Cell 136, 235 (2009). surprise that interference with autophagy tion and calcium influx, Goginashvili et 12. M. Kone et al., FASEB J. 28, 4972 (2014). al. show that a catastrophic event such as 13. L. Guariguata et al., Diabetes Res. Clin. Pract. 103, 137 cell death and lysis (which would allow in(2014). Section of Cell Biology and Functional Genomics, Division of sulin to leach out of the cell) is unlikely to 14. American Diabetes Association, Diabetes Care 36, 1033 Diabetes, Endocrinology and Metabolism, Imperial College (2013). be the explanation for enhanced insulin seLondon, Hammersmith Hospital, London W12 0NN, UK. cretion when autophagy is activated. Like10.1126/science.aaa6810 E-mail: [email protected] SCIENCE sciencemag.org
20 FEBRUARY 2015 • VOL 347 ISSUE 6224
Published by AAAS
827
Pancreas micromanages autophagy Guy A. Rutter Science 347, 826 (2015); DOI: 10.1126/science.aaa6810
This copy is for your personal, non-commercial use only.
If you wish to distribute this article to others, you can order high-quality copies for your colleagues, clients, or customers by clicking here.
The following resources related to this article are available online at www.sciencemag.org (this information is current as of February 19, 2015 ): Updated information and services, including high-resolution figures, can be found in the online version of this article at: http://www.sciencemag.org/content/347/6224/826.full.html A list of selected additional articles on the Science Web sites related to this article can be found at: http://www.sciencemag.org/content/347/6224/826.full.html#related This article cites 14 articles, 6 of which can be accessed free: http://www.sciencemag.org/content/347/6224/826.full.html#ref-list-1 This article appears in the following subject collections: Cell Biology http://www.sciencemag.org/cgi/collection/cell_biol
Science (print ISSN 0036-8075; online ISSN 1095-9203) is published weekly, except the last week in December, by the American Association for the Advancement of Science, 1200 New York Avenue NW, Washington, DC 20005. Copyright 2015 by the American Association for the Advancement of Science; all rights reserved. The title Science is a registered trademark of AAAS.
Downloaded from www.sciencemag.org on February 19, 2015
Permission to republish or repurpose articles or portions of articles can be obtained by following the guidelines here.
